The present invention, in some embodiments thereof, relates to methods of regulating angiogenesis by up or down regulation of Apolipoprotein B (apoB).
Angiogenesis is the formation of new blood vessels from pre-existing vasculature. Angiogenesis is relevant not only to cancer but also to non-neoplastic diseases such as: macular degeneration, psoriasis, endometriosis, arthritis and cardiovascular disease. The growth and metastasis of tumors are dependent upon angiogenesis. Therefore, inhibiting angiogenesis can be used as a method of retarding tumor progression.
Endothelial cells are the building blocks of blood and lymphatic vessels. The interaction between vascular endothelial growth factor (VEGF), which is secreted by tumor cells, and their receptors initiates signaling pathways leading to angiogenesis, including tumor-related angiogenesis. VEGF promotes endothelial cell survival, proliferation, and migration, mainly through the activation of the Flk-1 receptor.
Previous studies have shown that vascular endothelial growth factor receptor 1 (VEGFR1) plays an inhibitory role in angiogenesis, acting as a “sink” for the VEGF ligand [Hiratsuka, S., et al., Proceedings of the National Academy of Sciences of the United States of America 95, 9349-9354 (1998); Kearney, J. B., et al. Blood 99, 2397-2407 (2002); Chappell, J. C., et al., Developmental cell 17, 377-386 (2009)].
Apolipoprotein B (apoB) is a non-exchangeable apolipoprotein found associated exclusively with plasma lipoproteins. In the human genome there is one apob gene of less than 45 kb. In the liver, it is transcribed into a single mRNA of 15 kb and is translated into a single polypeptide of 4536 amino acids called apoB-100. In the intestine, the apoB mRNA is post-transcriptionally edited, resulting in the conversion of a glutamine codon into a stop codon. The edited mRNA is translated into a single polypeptide of 2,152 amino acids called apoB48.
Microsomal triglyceride transfer protein (MTP), an intraluminal protein found within the endoplasmic reticulum of liver and intestine, is required for assembly and secretion of proatherogenic-, apoB-containing lipoproteins such as chylomicrons, very low-density lipoproteins (VLDLs), and low-density lipoproteins (LDLs). Following their assembly as mature particles, apoB-lipoproteins are secreted to the blood and lymph stream by MTP.
U.S. patent applications Ser. No. 20110189300 and 20110003713 teach siRNA molecules that silence ApoB expression and methods of using such siRNAs for the treatment of atherosclerosis, angina pectoris, high blood pressure, diabetes, and hypothyroidism.
U.S. patent application Ser. No. 20050222029 teaches a method of treating cancer by preventing the interaction of ApoB with APOA1.
U.S. patent application Ser. No. 20120053128 teaches a method of inhibiting angiogenesis in mammals using a dimer peptide of apolipoprotein E.
Additional background art includes Salomonsson L. et al., Atherosclerosis. 2003 August; 169(2):259-67.